In Deinococcus radiodurans and other resistant bacteria, a mechanistic link exists between resistance, manganese accumulation, and protein protection. We previously demonstrated that ultrafiltered, protein-free preparations of D. radiodurans cell extracts prevent protein oxidation at massive doses of ionizing radiation. The two key protective components of the extract were peptides/amino acids and manganese. Having completed a systematic study of the contribution of each of the 20 common amino acids to protection of enzymes from inactivation, we applied the results to design peptide(s) with improved radioprotective properties. Since the aromatic and sulfur-containing amino acids were far superior to all others in providing protection, we studied peptides containing multiples of methionine and histidine. The hexapeptide Met-His-Met-His-Met-His was remarkably more protective than the decapeptide utilized in prior studies. In the absence of the hexapeptide, 2 kilogray caused loss of 50% of the activity of a purified enzyme, glutamine synthetase. In the presence of 1.6 mM hexapeptide, the dose required for half-inactivation increased to 112 kilogray. These studies also established that manganese had minimal influence on the protection provided by the peptides and amino acids. However, several previous publications provided experimental evidence for the importance of manganese in radioresistance. Thus, at present it appears that Deinococcus radiodurans has at least two independent mechanisms for resistance, one being manganese-dependent and the other being manganese-dependent.